Terfenadine, 1-(p-tert-butylphenyl)-4-[4'-(.alpha.-hydroxydiphenylmethyl)-1'-piperidiny l]butanol, is a non-sedating antihistamine. Previous crystallization procedures for terfenadine produce a product which, although analytically pure, nevertheless has widely variable melting point. Recently, it was discovered that solid terfenadine exists in two distinct crystalline or polymorphic forms, each form having a different melting point. It was further discovered that terfenadine crystallized by the prior art processes varies widely in polymorphic composition and that this polymorphic variation accounted for the observed variation of the melting point of terfenadine. Applicants have now discovered processes for preparing polymorphically pure terfenadine. These processes provide material with a controlled set for physical properties which should facilitate quanlity control functions associated with large scale production of terfenadine.
The higher melting polymorph of terfenadine is prepared by dissolving terfenadine in a water-miscible, lower alkanol, heating the solution at about its reflux temperature, slowly adding a sufficient quantity of water with stirring to effect crystal formation of substantially all of the dissolved terfenadine, cooling to about 25.degree. C. and collecting the crystalline product. The lower melting polymorph of terfenadine is prepared by dissolving terfenadine in a suitable solvent at about 0.degree. C. to about 35.degree. C., allowing the solvent to slowly evaporate and collecting the resulting crystalline product.